The mesolimbic dopamine (DA) system has been implicated in mediating the acute behavioral effects of various drugs of abuse as well as the development of drug-dependence and sensitization. It is these latter effects which have been implicated in the drug-craving and the reinstatement of compulsive drug-seeking behavior. Evidence that the activity of this system is regulated by opioid systems has also been presented. Ongoing studies seek to: 1) determine whether manipulations of opioid peptide systems modify the development of drug dependence and sensitization as expressed both behaviorally and neurochemically; 2) identify the location of those opioid systems which modulate mesolimbic activity and 3) determine the role of other neurotransmitter systems in mediating the interaction of opioid peptide systems with drugs of abuse. The resultant data is being used to identify pharmacological interventions for the treatment of stimulant as well as opiate abuse. Assessment of various drug-induced behaviors (IV self administration place preference conditioning, locomotor activity) has revealed that both the rewarding and psychomotor stimulant effects of cocaine and morphine are enhanced in animals with a prior history of drug exposure and that such sensitization increases as abstinence progresses. Neurochemical studies (microdialysis/HPLC and electrochemical detection) have demonstrated that there is also a progressive increase in the response of mesolimbic dopamine neurons to a subsequent drug challenge. Upon administration of synthetic kappa-opioid receptor agonists as well as metabolic fragments of dynorphin, the endogenous ligand for this receptor, these behavioral and neurochemical response to cocaine but not morphine are prevented. Administration of antagonists for the delta- opioid receptor prevent sensitization to both cocaine and morphine and exacerbate the aversive effects of opioid withdrawal. Mapping studies are currently in progress to determine the neuroanatomical sites which underlie the modulatory actions of these opioid peptide systems as well as those neurochemical alterations which underlie their efficacy in attenuating those effects associated with repeated stimulant and opioid use.